DESCRIPTION: The proposed project will map and identify genes defective in familial spastic paraplegia (FSP). Autosomal recessive, dominant, and X-linked forms of FSP exist, but only the X-linked genes have been identified. There is genetic heterogeneity in autosomal FSP, with autosomal dominant loci at 14q, 2p, and 15q (FSP1, FSP2, and FSP3 respectively) and an autosomal recessive locus at 8q. Other autosomal dominant and recessive FSP families do not map to any of the defined loci. The applicants have gathered samples from a set of FSP families and other resources to identify FSP genes. They will seek an additional FSP locus (FSP4) by genome-wide linkage analysis in two large autosomal dominant FSP families in which known loci have been excluded. They will localize and study candidate genes (known genes and ESTs) mapped to the most important FSP locus, FSP2 at chromosome 2p21-24. If necessary, cDNA selection techniques will be used to identify additional transcripts, taking advantage of a YAC contig the applicants have constructed for this locus. Based on evidence of anticipation in autosomal dominant FSP, trinucleotide repeat expansion is suspected; this possibility will be pursued with techniques designed to detect and identify expanded repeats. Finally, a new autosomal recessive FSP locus will be sought by linkage analysis of families unlinked to 8q.